中國(guó)科學(xué)院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所，中國(guó)科學(xué)院干細(xì)胞生物學(xué)重點(diǎn)實(shí)驗(yàn)室發(fā)育與疾病研究組于近日在國(guó)際著名學(xué)術(shù)期刊《血液》（Blood）在線發(fā)表了最新研究成果“Dominant-Negative C/ebpα and Polycomb Group Protein Bmi1 Extends Short-Lived Hematopoietic Stem/Progenitor Cells Lifespan and Induces Lethal Dyserythropoiesis”,。該項(xiàng)研究利用斑馬魚(yú)這一模式生物,，研究了造血發(fā)育和白血病發(fā)生過(guò)程中的關(guān)鍵調(diào)控因子C/ebpα和Bmi1在早期造血干/祖細(xì)胞生存和自我更新能力維持方面的作用,，并建立了造血發(fā)育異常的斑馬魚(yú)疾病模型,。該項(xiàng)成果為了解造血干細(xì)胞自我更新的分子調(diào)控路徑,，并進(jìn)一步探索造血系統(tǒng)發(fā)育和疾病發(fā)生的機(jī)制提供了新的依據(jù),。
該研究組博士研究生周婷同學(xué)在劉廷析研究員的指導(dǎo)下,，利用早期造血組織特異性的lmo2啟動(dòng)子和Cre-loxP系統(tǒng),，在斑馬魚(yú)早期造血干/祖細(xì)胞（primitive hematopoietic stem/progenitor cells）中特異性地表達(dá)白血病關(guān)鍵因子C/ebpα的顯性負(fù)蛋白和Bmi1蛋白,。發(fā)現(xiàn)顯性負(fù)的C/ebpα蛋白（Dominant-Negative C/ebpα）可以使這群自我更新能力有限的短程干細(xì)胞（short-lived stem cells）的細(xì)胞壽命延長(zhǎng)至胚胎定向造血（definitive hematopoiesis）階段,，并進(jìn)而誘發(fā)紅系造血異常（erythropoietic dysplasia）,。進(jìn)一步研究證實(shí)：C/ebpα蛋白可通過(guò)結(jié)合Bmi1基因啟動(dòng)子區(qū)的C/EBP結(jié)合序列，使C/ebpα顯性負(fù)轉(zhuǎn)基因魚(yú)系的Bmi1表達(dá)特異性上升;在斑馬魚(yú)早期造血干/祖細(xì)胞特異性過(guò)表達(dá)Bmi1可獲得與C/ebpα顯性負(fù)轉(zhuǎn)基因魚(yú)系非常相似的表型，反之則可以使該異常表型基本消失,。這些結(jié)果提示：表觀遺傳學(xué)調(diào)控因子Bmi1可能是C/ebpα蛋白的直接下游，顯性負(fù)的C/ebpα蛋白正是通過(guò)上調(diào)Bmi1影響早期造血干/祖細(xì)胞的生存及自我更新能力,。
該工作得到國(guó)家科技部、國(guó)家自然科學(xué)基金委,、上海市科委,、中國(guó)科學(xué)院以及上海市教委E-研究院的經(jīng)費(fèi)支持。(生物谷 Bioon.com)
doi:10.1182/blood-2010-12-327908
PMC:
PMID:
Dominant-negative C/ebpα and polycomb group protein Bmi1 extends short-lived hematopoietic stem/progenitor cells lifespan and induces lethal dyserythropoiesis
Ting Zhou, Lei Wang, Kang-Yong Zhu, Mei Dong, Peng-Fei Xu, Yi Chen, Sai-Juan Chen, Zhu Chen, Min Deng, and Ting Xi Liu
The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are believed to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into "long-lived" in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpα (C/ebpαDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their lifespan, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality due to circulation congestion. Mechanistically, C/ebpαDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpαDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrant phenotypes induced by C/ebpαDN, while knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediate downstream of C/ebpαDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia.
